Effects of a clinical metagenomics intervention on clinical outcomes, healthcare costs, and health-related quality of life in patients with sepsis or septic shock: results of the randomized-controlled DigiSep trial.

Summary

In this multicenter RCT, adding mNGS-based pathogen detection to standard sepsis diagnostics did not improve the primary DOOR/RADAR endpoint but reduced duration of mechanical ventilation and shock and improved 90-day health-related quality of life, with no increase in 180-day healthcare costs. These results suggest clinically meaningful benefits in secondary outcomes with neutral cost impact.

Key Findings

• Primary DOOR/RADAR endpoint at 28 days showed no significant improvement with mNGS.
• Mechanical ventilation duration was reduced (6.6 vs 9.3 days; 95% CI −5.03 to −0.34).
• Shock resolved earlier (6.9 vs 8.8 days; 95% CI −3.75 to −0.04).
• EQ-5D-5L at 90 days improved (0.312 vs 0.208; p=0.047) with no increase in 180-day healthcare costs.

Clinical Implications

mNGS may be selectively integrated as an adjunct to standard microbiology to expedite clinical stabilization and recovery in sepsis, though primary composite benefit was not proven; guideline changes will likely await confirmatory trials.

Limitations

• Open-label design with risk of performance bias
• Primary endpoint neutral; secondary analyses exploratory with multiplicity concerns and limited cost data subset

Future Directions

Conduct confirmatory, possibly blinded, trials targeting patient-centered endpoints and antimicrobial stewardship metrics, and define patient subgroups with the greatest benefit from mNGS-guided care.